Von Willebrand disease type Vicenza: In search of a classification for the archetype of reduced von Willebrand factor survival.

Alessandra Casonato,Federico Galvanin,Viviana Daidone,Eva Galletta

doi:10.1002/jha2.196

Abstract

Type Vicenza von Willebrand disease (VWD) features a von Willebrand factor (VWF) with a very short half‐life, and is classified as a form of type 1 VWD. To test the appropriateness of type Vicenza VWD classification, the main features of 17 patients from eight unrelated families were analysed. They had low VWF antigen levels and function (always below 20 U/dl); ristocetin‐induced platelet aggregation sometimes normal, sometimes reduced/absent (even in the same patient); normal platelet VWF levels; an increased VWF propeptide to VWF antigen ratio (8.74 ± 1.65 vs. normal 1.04 ± 0.28) and a reduced VWF half‐life. Plasma VWF multimer levels were homogeneously reduced, and unusually large VWF multimers were sometimes present. Recombinant p.R1205H VWF showed a normal synthesis, release, function, and multimer pattern, with no ultra‐large VWF multimers. The mathematical model by Galvanin et al. was used to explore the kinetic changes in VWF after DDAVP. It showed that the release, but especially the proteolysis (k proteol 1.0−3 ± 2.5−3 vs. normal 4.5−4 ± 6.4−4) and elimination (k el 1.0−2 ± 5.2−3 vs. normal 1.1−3 ± 6.8−4) of type Vicenza VWF were significantly higher than normal. The increased elimination is consistent with the short half‐life, while the increased proteolysis was unexpected. As a shorter survival of VWF is wholly responsible for the type Vicenza VWD phenotype (VWF synthesis, structure and function are normal), it might be better to classify it as a type 2 VWD (rather than type 1) to emphasise the greater interaction with clearance receptors as a new VWF functional defect.

Highlights

Platelet plug formation at the site of vascular injury is guaranteed by the contribution of von Willebrand factor (VWF), a multimeric glycoprotein capable of forming a bridge between the subendothelial matrix and platelets, as well as promoting platelet interactions [1]
Bleeding symptoms were quantified by the ISTH bleeding assessment tool (BAT): the scores were higher in patients than in healthy controls, with no difference between females (10.5 ± 5.1 vs. normal range 0–5) and males (11.5 ± 6.0 vs. normal 0–3)
We examine whether it is appropriate to classify type Vicenza as a type 1 von Willebrand disease (VWD), considering all of its known in vivo and in vitro features, with the aid of a mathematical model

Summary

Introduction

Platelet plug formation at the site of vascular injury is guaranteed by the contribution of von Willebrand factor (VWF), a multimeric glycoprotein capable of forming a bridge between the subendothelial matrix and platelets, as well as promoting platelet interactions [1]. Type 1 VWD is defined as a partial quantitative VWF defect, with the residual VWF featuring no functional abnormalities, and a normal or near-normal multimer pattern [4,5,6]. The large VWF multimers were all present, sometimes with the presence of unusually large VWF oligomers as well [8] It was later reclassified as type 2M VWD because of the abnormal ristocetin-induced platelet aggregation (RIPA) seen in these patients. An accelerated VWF clearance seems to be the only explanation for the presence of ultra-large multimers in type Vicenza VWD [13]. It is classified once again as a type 1 VWD, based on low circulating VWF levels and the presence of all VWF multimers [3]

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